Fluoranthene derivatives

ABSTRACT

The present invention relates to compounds of formula (I) 
     
         ArCH.sub.2 R.sup.1                                         (I) 
    
     or a monomethyl or a monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 30 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar is a fluoranthene or substituted fluoranthene ring system; R 1  contains not more than eight carbon carbon atoms and is a group ##STR1## wherein m is 0 or 1; 
     R 5  is hydrogen; 
     R 6  and R 7  are the same or different and each is hydrogen or C 1-3  alkyl optionally substituted by hydroxy; 
     R 8  and R 9  are the same or different and each is hydrogen or C 1-3  alkyl; 
     --C--C-- is a five- or six-membered saturated carbocyclic ring; 
     R 10  is hydrogen, methyl or hydroxymethyl; 
     R 11 , R 12  and R 13  are the same or different and each is hydrogen or methyl; 
     R 14  is hydrogen, methyl, hydroxy, or hydroxymethyl.

This is a divisional of co-pending application Ser. No. 661,674 filed onOct. 17, 1984, now U.S. Pat. No. 4,720,587 which is acontinuation-in-part of application Ser. No. 496,853, now U.S. Pat. No.4,532,344.

The present invention relates to polycyclic aromatic alkanol derivativeswhich have been found to have biocidal activity. More specifically theinvention concerns aminoalkanol derivatives containing a polycarbocyclicaromatic ring system, methods for the synthesis thereof, pharmaceuticalformulations thereof, novel intermediates therefor, pharmaceuticalformulations thereof and the use thereof as biocidal agents,particularly antitumor agents.

Accordingly, in a first aspect, the present invention provides acompound of the formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I)including these ethers may contain no more than 30 carbon atoms intotal); ethers, esters thereof; acid addition salts thereof;

wherein

Ar is a fluoranthene ring optionally substituted by one or twosubstituents (the substituents will contain not more than four carbonatoms in total when taken together being the same or different and areselected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionallysubstituted by hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl orC₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 andR² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; orthe fluoranthene ring is optionally substituted by a group NR³ R⁴containing not more than 5 carbon atoms wherein R³ and R⁴ are the sameor different and each is a C₁₋₃ alkyl group or NR³ R⁴ forms a five- orsix-membered heterocyclic ring optionally containing one ot twoadditional heteroatoms);

R¹ contains not more than eight carbon atoms and is a group ##STR2##wherein m is 0 or 1;

R⁵ is hydrogen;

R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₃ alkyloptionally substituted by hydroxy;

R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl;

--C--C-- is a five- or six-membered saturated carbocyclic ring;

R¹⁰ is hydrogen, methyl or hydroxymethyl;

R¹¹, R¹² and R¹³ are the same or different and each is hydrogen ormethyl;

R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.

Suitably ArCH₂ R¹ or a monomethyl or monethyl ether thereof contains notmore than 28 carbon atoms in total.

Ar is suitably 3- or 7-fluoranthenyl, ##STR3## suitably m is 0, suitablyR¹ is ##STR4## wherein R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH,

R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH;

R¹⁸ is hydrogen or methyl.

Preferably R¹⁶ is CH₂ OH or CH(CH₃)OH; R¹⁷ is hydrogen, methyl, ethyl orCH₂ OH; Ar is 3-fluoranthenyl.

Most preferably R¹ is a diol of the structure ##STR5## wherein R¹⁹ ishydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl, preferablymethyl.

Acid addition salts included within the scope of the present inventionare those of compound of formula (I) and ethers and esters thereof.

Esters and nonpharmaceutically useful acid addition salts of thecompounds of the formula (I) are useful intermediates in the preparationand purification of compounds of the formula (I) and pharmaceuticallyuseful acid addition salts thereof, and are therefore within the scopeof the present invention. Thus, acid addition salts of the compounds ofthe formula (I) useful in the present invention include but are notlimited to those derived from inorganic acids, such as hydrochloric,hydrobromic, sulfuric and phosphoric acids, and organic acids such asisethionic (2-hydroxyethylsulfonic), maleic, malonic, succinic,salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,naphthalene-2-sulfonic, and ascorbic acids, and amino acids such asglycine. Acid addition salts particularly useful as biocidal agents arethose that are pharmacologically and pharmaceutically acceptable. Thus,suitable acid addition salts include but are not limited to thosederived from hydrochloric, methanesulfonic, ethanesulfonic, isethionic,lactic and citric acids.

The preferred pharmacologically and pharmaceutically acceptable saltsare those that are soluble in solvents suitable for parenteraladministration, for example, hydrochlorides, methanesulfonates andisethionates.

Esters of compounds of formula (I) are derived from acids known to thoseskilled in the art to be suitable for ester formation, and areconveniently those derived from C₁₋₆ alkanoic acids or alkanoic acidderivatives, for example acetic acid, propionic acid, n-butyric acid andiso-butyric acid. The esters may be formed from all or only some of thehydroxy groups contained in the compounds of formula (I). Specificcompounds within the scope of formula (I) include;

2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol,

2-((3-Fluroanthenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol,

2-Ethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediol,

2-((7-Fluoranethenylmethyl)amino)-2-methyl-1,3-propanediol,

3-Methoxy-2-((3-fluoranthenylmethyl)amino)-2-methyl-1-propanol,

(+-)(2R*,3S*)-2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-butanediol,

2-Ethoxymethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediol,

(1α,2β,3α)-2-((3-Fluoranthenylmethyl)amino)-1,3-cyclohexanediol,

2-((3-Fluoranthenylmethyl)amino)-2-isopropyl-1,3-proanediol,

2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,4-butanediol,

2-((4-Ethyl-3-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol,

2-((3-Fluoranthenylmethyl)amino)-2-methyl-1-propanol,

2-((8-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol,

2-(((3-Chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and

2-(((4-Chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol,

2-(((3-Ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and

2-(((4-Ethyl-8-fluroanthenyl)methyl)amino)-2-methyl-1,3-propanediol;

ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), preferredcompounds are 2-((3-fluoranthenylmethyl)amino-2-methyl-1,3-propanediol,(+-)(2R*,3S*)-2-((3-fluroanthenylmethyl)amino)-2-methyl-1,3-butanediol,and 2-((3-fluoranthenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol;ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the mostpreferred compound is2-((3-fluoranthenylmethyl)amino-2-methyl-1,3-propanediol; ethers, estersthereof; acid addition salts thereof.

The compounds of formula (I) and their ethers, esters and salts thereofmay be prepared by any method known in the art for the preparation ofcompounds of analogous structure. Thus, the compounds of formula (I)may, for example, be prepared by any of the methods defined below.

1. The reduction of a compound of formula (II) ##STR6## wherein R¹ -R⁴are as hereinbefore defined or an appropriately protected derivativethereof followed by deprotection where appropriate.

The conditions and reagents for such a reaction are well known to thoseskilled in the art, and any such conditions/reagents may be employed.The conversion of (II) or suitably protected derivatives thereof may becarried out by a reducing agent followed by deprotection if necessary.The reduction is conveniently carried out by a metal hydride such aslithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,or by catalytic hydrogenation, conveniently by hydrogen in the presenceof a metal catalyst such as palladium or platinum, or equivalentreagents as outlined by J. March, Advanced Organic Chemistry, 2nd ed.,pages 819-820, McGraw Hill, New York, 1977. The reduction is suitablycarried out with the compound of formula (II) in solution in an inertsolvent or mixture of solvents compatible with the reducing agent, at anon-extreme temperature, for example, between 0° and 80° C.,conveniently at room temperature.

In the case of lithium aluminum hydride and like reagents, suitablesolvents include ethers (for example tetrahydrofuran, diethyl ether and1,2 -dimethoxyethane) optionally in the presence of a hydrocarboncosolvent (for example toluene, benzene or hexane).

In the case of sodium borohydride and like reagents, suitable solventsinclude alcohols (for example ethanol, methanol or isopropanol)optionally in the presence of a hydrocarbon cosolvent (for exampletoluene, benzene or hexane) or an ether cosolvent (for examplediethylether or tetrahydrofuran).

In the case of sodium cyanoborohydride and like reagents, suitablesolvents include those described for sodium borohydride and in thepresence of an acid conveniently glacial acetic acid or ethanolichydrochloric acid as outlined in, for example, R Hutchins et al.,Organic Preparations and Procedures International 11, 201 (1979).

In the case of catalytic hydrogenation, suitable solvents includealcohols (for example methanol and ethanol) optionally in the presenceof a hydrocarbon cosolvent (for example toluene or benzene) or ethercosolvent (for example diethyl ether or tetrahydrofuran) in the presenceof an acid (for example glacial acetic acid or ethanolic hydrochloricacid) or in glacial acetic acid.

Protected derivatives of compounds of formula (II) are conveniently usedwhen lithium aluminum hydride is employed as the reducing agent.Convenient protecting groups are compatible with the reducing agentutilized and are readily removed under nondestructive conditions, forexample benzyl, tetrahydropyranyl and isopropylidene ethers.

It is often convenient not to isolate the compound of the formula (II)but to react a compound of the formula (III) with a compound of theformula (IV): ##STR7## wherein Ar and R¹ -R⁴ are as defined in (I), andreduce the compound of the formula (II) so formed in situ. The reactionof the compounds of the formulae (III) and (IV) is again suitablycarried out using conditions and reagents which are well known to thoseskilled in the art, for example in the presence of an acid, such as asulfonic acid, i.e. p-toluenesulfonic acid, in an appropriate inertsolvent, such as an aromatic hydrocarbon, suitably toluene, withazeotropic removal of water followed by treatment with the reducingagent in an appropriate solvent, suitably ethanol or methanol.Alternatively, (II) formed under equilibrium conditions in appropriatesolvents can be reduced in situ with an appropriate reducing agent,suitably sodium cyanoborohydride.

The compound of formula (III) may be in the form of a protectedaldehyde, for example an acetal, which liberates the aldehyde functionunder the reaction conditions.

In turn, a compound of formula (III) can be synthesized by reacting theappropriate polycyclic aromatic hydrocarbon with a formylating agentsuch as that generated by the reaction between SnCl₄ and Cl₂ CHOCH₃ orequivalent reagents, for example, according to the method of A. Reicheet al., Chem. Ber. 93, 88 (1960), or with other standard formylatingreagents/procedures known to the art, for example, the Gatterman-Kochreaction (CO/HCl/AlCl₃ /CuCl), the Gatterman reaction (HCN/HCl/ZnCl₂),and the Vilsmeier reaction (POCl₃ /PhN(Me)CHO, or POCl₃ /Me₂ NCHO) (J.March, vide supra, pages 494-497).

The compounds of the formula (III) may also be prepared from anappropriate polycyclic aromatic hydrocarbon substituted by a suitablefunctional group such as CH₂ OH, CHBr₂, CH₃, COCH₃, COOH, or CN, andconverting this functional group to an aldehyde group by methods wellknown to those skilled in the art. Where the polycyclic aromatic ringbears substituents, the compound of formula (III) may be prepared by avariety of methods known in the art of organic chemistry depending onthe nature of the substituent on the polycyclic ring. For example, ifthe substituent(s) is a halogen, the starting materials may be preparedby direct treatment of the polycyclic aromatic hydrocarbon with ahalogenating agent (e.g. Cl₂, Br₂, or SO₂ Cl₂) or indirectly by suchroutes as the Sandmeyer reaction (H. H. Hodgson, Chem. Rev. 40, 251(1947). If the substituent(s) is alkyl, the polycyclic Taromatichydrocarbon may be reacted with the appropriate reagents underFriedel-Crafts reaction conditions (G. A. Olah, Friedel Crafts andRelated Reactions, Vols. 1-3, Interscience, New York, NY, 1963-1965).

The compounds of the formula (IV) may also be prepared by methods knownin the art, for example, by the reaction of compound NO₂ CH₂ R^(`) withan appropriate aldehyde, conveniently acetaldehyde or formaldehyde (asin B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940))followed by reduction (as outlined in J. March, vide supra, pages1125-1126), conveniently by hydrogen and a metal catalyst (for example,a platinum containing catalyst) in an appropriate solvent, convenientlyglacial acetic acid.

2. The reduction of a compound of the formula (V) ##STR8## wherein Arand R¹ -R⁴ are as hereinbefore defined and the hydroxy groups areoptionally protected, followed by deprotection of the hydroxy groupswhere appropriate. The reduction may be carried out by standard reducingagents known for carrying out this type of reduction (as outlined in J.March, vide supra page 1122), for example, a hydride reagent such aslithium aluminium hydride in an inert solvent, such as an ether, i.e.tetrahydrofuran, at a non-extreme temperature, for example, at between0° and 100° C. and conveniently at the reflux temperature of the ether.

The compound of the formula (V) may be formed by the reaction of theappropriate acid (ArCOOH) or a suitable reactive acid derivative thereof(as outlined in J. March. vide supra, pages 382-390), for example, anacid halide, in an inert solvent with an amine of the formula (IV) inwhich the hydroxy groups are optionally protected, for example, when thecompound of the formula (IV) is a diol, by an isopropylidene group. Thecompound of the formula (V) so formed is suitably reduced in situ anddeprotected if necessary to give a compound of formula (I). Thecompounds of the formula ArCOOH can be prepared by methods well known tothose skilled in the art.

3. The reaction of a compound ArCH₂ L (wherein Ar is as hereinbeforedefined and L is a leaving group) with a compound of the formula (IV) ashereinbefore defined. Suitable leaving groups are those defined by J.March, vide supra, pages 325-331, and include halogens such as chlorineand bromine and sulfonic acid derivatives such as p-toluenesulfonate.The reaction is suitably carried out in an appropriate solvent, such asa dipolar aprotic solvent or alcohol at a non-extreme temperature, forexample 50°-100°. The compounds of the formula ArCH₂ L can be preparedby methods well known to those skilled in the art.

There is therefore provided, as a further aspect of the invention, amethod for the preparation of a compound of formula (I) comprising anymethod known for the preparation of analogous compounds, in particularthose methods defined in (1) to (3) hereinabove.

The compounds of this invention have biocidal activity, e.g. are toxicto certain living cells which are detrimental to mammals, for examplepathogenic organisms and tumor cells. This toxicity to pathogenicorganisms has been demonstrated by activity against viruses (e.g. Herpessimplex 1/vero), fungi (e.g. Candida albicans), protozoa (e.g. Eimeriatenella and Trichomonas vaginalis), bacteria (e.g. Mycoplasma smegmatisand Streptococcus pyogenes), and helminths (e.g. Nippostrongylusbrasiliensis). The antitumor activity of compounds of formula (I) hasbeen demonstrated in a number of recognized screens and primarily byactivity against ascitic P388/0 leukemia.

Preferred compounds of the formula (I) are those which have antitumoractivity. The activity against ascitic tumors, including P388/0, isevidenced by reduction of tumor cell number in mammals (for example,mice bearing ascitic tumors) and their consequent increase in survivalduration as compared to an untreated tumor bearing control group.Antitumor activity is further evidenced by measurable reduction in thesize of solid tumors following treatment of mammals with the compoundsof this invention compared to the tumors of untreated control tumorbearing animals. Compounds of formula (I) are active against murinetumors such as lymphocytic leukemia P388/0, lymphocytic leukemia L1210,melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma, colon 38adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lung carcinoma.

Activity in one or more of these tumor tests has been reported to beindicative of antitumor activity in man (A. Goldin et al. in Methods inCancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, AcademicPress, N.Y. 1979).

There are sublines of P388/0 which have been made resistant to thefollowing clinically useful agents: cytosine arabinoside, doxorubicin,cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil,actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds ofthis invention show potent activity against these drug-resistant tumoursusing the procedure for P388/0 above.

Compounds of formula (I) have also been found to be active against humantumor cells in primary cultures of lung, ovary, breast, renal, melanoma,unknown primary, gastric, pancreatic, mesothelioma, myeloma, and coloncancer. (As used herein "cancer" is to be taken as synonymous with"malignant tumor" or more generally "tumor" unless otherwise noted.)This is a procedure in which the prevention of tumor cell colonyformation, i.e. tumor cell replication, by a drug has been shown tocorrelate with clinical antitumor activity in man (D. D. Von Hoff etal., Cancer Chemotherapy and Pharmacology 6, 265 (1980); S. Salmon andD. D. Von Hoff, Seminars in Oncology, 8, 377 (1981)). Compounds offormula I which have been found to have antitumor activity intercalatein vitro with DNA (this property is determined by viscometric methodsusing the procedure of W. D. Wilson et al., Nucleic Acids Research 4,2697 (1954)) and a log P as calculated by the method of C. Hansch and A.Leo in Substituent Constants for Correlation Analysis in Chemistry andBiology, John Wiley and Sons, New York, 1979, lying in the range between-2.0 and +2.5.

As has been described above, the compounds of the present invention areuseful for the treatment of animals (including humans) bearingsusceptible tumors. The invention thus further provides a method for thetreatment of tumors in animals, including mammals, especially humans,which comprises the administration of a clinically useful amount ofcompound of formula (I) in a pharmaceutically useful form, once orseveral times a day or other appropriate schedule, orally, rectally,parenterally, or applied topically.

In addition, there is provided as a further, or alternative, aspect ofthe invention, a compound of formula (I) for use in therapy, for exampleas an antitumor agent.

The amount of compound of formula (I) required to be effective as abiocidal agent will, of course, vary and is ultimately at the discretionof the medical or veterinary practitioner. The factors to be consideredinclude the condition being treated, the route of administration, thenature of the formulation, the mammal's body weight, surface area, ageand general condition, and the particular compound to be administered. Asuitable effective antitumor dose is in the range of about 0.1 to about120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg,for example 10 to 30 mg/kg. The total daily dose may be given as asingle dose, multiple doses, e.g., two to six times per day, or byintravenous infusion for a selected duration. For example, for a 75 kgmammal, the dose range would be about 8 to 9000 mg per day, and atypical dose would be about 2000 mg per day. If discrete multiple dosesare indicated, treatment might typically be 500 mg of a compound offormula I given 4 times per day in a pharmaceutically usefulformulation.

While it is possible for the active compound (defined herein as compoundof formula (I), or ether, ester, or salt thereof) to be administeredalone, it is preferable to present the active compound in apharmaceutical formulation. Formulations of the present invention, formedical use, comprise an active compound together with one or morepharmaceutically acceptable carriers thereof and optionally othertherapeutical ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of formula (I) (in the form of thefree base, ether, or ester derivative or a pharmaceutically acceptableacid addition salt thereof) together with a pharmaceutically acceptablecarrier therefore.

There is also provided a method for the preparation of a pharmaceuticalformulation comprising bringing into association a compound of formula(I), an ether, ester, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier therefore.

While the antitumor activity of the compounds of formula (I) is belivedto reside in the free base, it is often convenient to administer an acidaddition salt of a compound of formula (I).

The formulations include those suitable for oral, rectal or parenteral(including subcutaneous, intramuscular and intravenous) administration.Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension in an aqueous liquid ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine, a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavorings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredient, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a pharmaceutically and pharmacologicallyacceptable acid addition salt of a compound of the formula (I) that isisotonic with the blood of the recipient. Thus, such formulations mayconveniently contain distilled water, 5% dextrose in distilled water orsaline and a pharmaceutically and pharmacologically acceptable acidaddition salt of a compound of the formula (I) that has an appropriatesolubility in these solvents, for example the hydrochloride, isethionateand methanesulfonate salts, preferably the latter.

Useful formulations also comprise concentrated solutions or solidscontaining the compound of formula (I) which upon dilution with anappropriate solvent give a solution suitable for parental administrationabove.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

The following examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof.

GENERAL COMMENTS

All solvents were reagent grade and used without further purificationwith the following exceptions. THF was dried by distillation from Na/Kalloy under nitrogen (N₂) and used immediately. Toluene (PhCH₃) wasdistilled from CaH₂ under N₂ and stored over 3Å molecular sieves.Chemicals used were reagent grade and used without purification unlessnoted. The full name and address of the suppliers of the reagents andchemicals is given when first cited. After this, an abbreviated name isused.

Preparative HPLC was carried out on a Water's Prep LC/System 500Amachine using two 500 g silica gel (SiO₂) cartridges unless otherwisenoted. Plugs of SiO₂ used for purification were "flash chromatography"SiO₂ (Merck & Co., Inc., Merck Chemical Division, Rahway, NJ, 07065,silica gel 60, 230-400 mesh). An appropriate volume sintered glassfunnel was filled approximately 3/4 full with the SiO₂ and packed evenlyby tapping the outside of the funnel. A piece of filter paper was thenplaced on top of the SiO₂ and a solution of the material to be purifiedapplied evenly to the top. Gentle suction through a filter flask movedthe eluting solvent through the plug rapidly. The appropriate sizefractions were combined as needed and further manipulated.

General procedures are described in detail. Analogous procedures showmelting point (mp), recrystallization solvents, and elemental analyses(all elements analyzing within a difference of ≦0.4% of the expectedvalue). Any changes to the procedure such as solvent, reactiontemperature, reaction time, or workup are noted.

NMR (¹ H, ¹³ C), IR, MS data of all new products were consistent withthe expected and proposed structures. The positions assigned tostructural isomers were unequivocally determined by a number of NMRtechniques. All final products were dried in a vacuum oven at 20 mm Hgpressure at the temperature indicated overnight (12-16 h). Alltemperatures are in degrees Celsius. Other abbreviatipns used are: roomtemperature (RT), absolute (abs.), round bottom flask (RB flask),minutes (min), hours (h).

EXAMPLE 1 2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride

Formylation of Fluoranthene

A 5 L 3-neck flask fitted with overhead mechanical stirrer, thermometer,condenser, and N₂ line was charged with fluoranthene (Aldrich ChemicalCo., Milwaukee, WI, 53201, 100 g, 0.49 mol) and CH₂ Cl₂ (700 mL). Aftercooling with a salt-ice bath to 5°, SnCl₄ (Aldrich, 98%, 250 g, 0.96mol, 112 mL) was added to the solution in one portion. No temperaturechange occurred. The flask temperature was kept below 5°, and1,1-dichloromethylmethylether (Aldrich, 67.6 g, 0.59 mol, 53 mL) wasadded dropwise over 1 h. The resulting suspension was warmed slowly toreflux (-37°) over 2 h and further stirred for 16 h. Considerable HClgas evolution occurred during the warming and the early part of thereaction at 37°. The reaction mixture was then cooled to 10° andhydrolysed by careful addition of 1 L of cold H₂). After 4 h the layerswere separated and the organic layer filtered, dried with anhydrous Na₂SO₄ (Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 100 g)and filtered again. The clear yellow solution was concentrated to give ayellow oil. The crude material was passed through a 1000 g plug of SiO₂using PhCH₃ as the eluting solvent (3 L). The fractions containing themixture of aldehydes were combined and the solvent removed giving 115 gof crude yellow oil. This material was dissolved in 500 mL of CH₂ Cl₂and diluted to 1 L with hexane. A yellow precipitate formed and wasisolated by filtration. This solid (which is 3-fluoranthenecarbaldehyde)was crystallized from CH₂ Cl₂ /hexane and dried at 50° to give 45.7 g ofpure material. The filtrate was added to the remaining impure mixtureand the solvent removed. The remainder of the material waschromatographed on a 1000 g plug of SiO₂ using PhCH₃ as eluting solventand the fractions further purified by preparative HPLC, again usingPhCH₃ as the eluting solvent. From this mixture, three aldehydes(including more of the 3-isomer) were obtained. The total amountsisolated, identity, and TLC behavior (SiO₂ /PhCH₃) of these aldehydesare shown below.

1A. 3-Fluoranthenecarbaldehyde 68.73 g (61%) mp 103°-104.5°, (Rf=0.27),(C, H), (lit. mp 98°-99°, N. Campbell and N. H. Wilson, Chem. and Ind.1114 (1970).

1B. 7-Fluoranthenecarbaldehyde 2.10 g (2%) mp 139°-141°, (C, H), Rf=0.38

1C. 8-Fluoranthenecarbaldehyde 24.8 g (22%) mp 91.5°-93°, (C, H),(Rf=0.19).

1D. 2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride

To a 2 L Erlenmeyer flask was added 3-fluoranthenecarbaldeyde (11.51 g,50 mmol) 2-methyl-2-amino-1,3-propanediol (Aldrich, 5.52 g, 52.5 mmol),p-toluenesulfonic acid.H₂ O (Eastman Kodak Co., Rochester, NY, 14650,0.1 g, 0.5 mmol), and PhCH₃ (500 mL). The mixture was warmed to refluxfor a few minutes and H₂ O (2-3 mL) was driven off. The resulting goldencolored solution was allowed to cool to RT, diluted with abs. EtOH (500mL) and stirred overnight. NaBH₃ CN (Aldrich, 95%, 1.57 g, 25 mmol) wasadded to the reaction. After the NaBH₃ CN dissolved, an indicator(bromocresol green, Eastman, 5 mg) was added. To the resulting added. Tothe resulting blue solution was added 5 drops of 1M solution of HCl gasin absolute EtOH every 15 minutes. After 3 days the indicator turnedgreen then yellow and voluminous white precipitate was present in theflask. To the flask was then added 1M HCl gas (10 mL) in abs. EtOH, andH₂ O (10 mL). The liquid was then removed by rotary evaporation to givea yellow solid. The solid was shaken with 20% HCl solution (500 mL) andcollected by filtration. The resulting solid was washed with additional20% HCl solution (250 mL) and then with CH₂ Cl₂ (4×250 mL), pressed andthen sucked dry. The slightly yellow solid was then recrystallized fromCH₃ OH/Et₂ O to give 11.80 g (66%) of2-((3-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloridemp 262°-265° (dec), (C, H, Cl, N).

EXAMPLE 2 2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride

Using the reductive amination procedure described in 1D,3-fluoranthenecarbaldehyde (1A) and tris(hydroxymethyl)aminomethane(Aldrich) gave 2-((3-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride mp 240°-241° (dec), (CH₃ OH/Et₂ O), (C, H, N, Cl).

EXAMPLE 3 2-Ethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediolhydrochloride

Using the reductive amination procedure described in 1D,3-fluoranthenecarbaldehyde (1A) and 2-amino-2-ethyl-1,3-propanediol(Aldrich) gave 2-ethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediolhydrochloride mp 250°-252° (dec), (CH₃ OH/Et₂ O), (C, H, Cl, N).

EXAMPLE 4 2-((7-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in 1D,7-fluoranthenecarbaldehyde (1B) and 2-amino-2-methyl-1,3-propanediol(Aldrich) gave 2-((7-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride mp 204°-206° (dec), (CH₃ OH/Et₂ O), (C, H, Cl, N).

EXAMPLE 5(+-)(2R*,3S*)-2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-butanediol

5A. (+-)(2R*,3S*)-2-Methyl-2-nitro-1,3-butanediol and

5B. (+-)(2R*,3R*)-2-Methyl-2-nitro-1,3-butanediol

To a mixture of 2-nitro-1-propanol (Aldrich, 63.0 g, 0.60 mol) andacetaldehyde (Eastman, 39.6 g, 0.90 mol) cooled in an ice bath under N₂was added cold H₂ O (40 mL) and calcium hydroxide (200 mg). The mixturewas allowed to warm to RT over 2 h and then stirred for 68 h. Theresulting solution was neutralized with excess solid CO₂. The mixturewas stirred for 1 h before filtration through a Millipore® filter. Thefiltrate was then concentrated under vacuum at 35°. The residue, aviscous syrup partially crystallized on drying under vacuum (0.1 mm, RT,48 h) was then triturated with cold Et₂ O (35 mL). Solid white crystalswhich formed were collected by filtration, washed with cold Et₂ O (3×15mL) and dried under vacuum (0.1 mm, RT) to give 34.1 g of material,judged by NMR to be (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (5A)(purity>97%, racemic). After recrystallization, the diastereoiomericpurity was >99%, mp 78.5°-81° (lit. 78°; cf. Beil 1, 482, in Henry,Bull. Soc. Chem. Fr. [3] 15, 1224), (C, H, N).

The original filtrate (including washes) was concentrated under vacuumto a pale yellow liquid which was subjected to flash chromatography asfollows: The sample was mixed with hexane/EtOAc (2:1, 100 mL) and addedto a column of dry SiO₂ (1.5 kg). The column was eluted withhexane/EtOAc (2:1, 12 L) then hexane/EtOAC (1:1, 6 L) while 500 mLfractions were collected. Appropriate fractions were combined. Pureproduct was found in the final 8 L; yield, 38.7 g of viscous syrup,judged by NMR to be a 1:1 mixture of the two racemic diastereomers (5Aand 5B), (C, H, N).

This and another batch of the 1:1 diasteriomeric mixture of 5A and 5B(prepared as described above) were combined (67 g, total) and subjectedto successive liquid-liquid partitioning between H₂ O and EtOAc to givepure samples (99% on the basis of NMR and HPLC (Hamilton PRP-1 columnusing 3.5% aqueous acetonitrile as the mobile phase)) of(+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (5A) (24.9 g, k'=4.3, mp79°-81°, C, H, N) and (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (5B)(15.8 g, k'=2.1, C, H, N, a colorless, viscous liquid).

5C. (+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane and

5D. (+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane

The relative configurations of the two diasteriomeric pairs (5A and 5B)were unequivocably assigned on the basis of comparative NMR analysis ofthe respective cyclic acetals derived from benzaldehyde. Thus, 5A (1.49g, 0.01 mol) and benzaldehyde (Mallinckrodt, 1.06 g, 0.01 mol) werecondensed in benzene in the presence of a catalytic amount ofp-toluenesulfonic acid (Fisher) with azeotropic removal of water(according to the method of H. Piotrowska, B. Serafin and T. Urbanski,Tetrahedron 109, 379 (1963)). After successive washing with satd. NaHCO₃solution, drying (MgSO₄), filtration, and removal of the benzene byrotary evaporation, a pale yellow solid was obtained. A solution of thisproduct in ethanol at 0° C. provided an oil which was isolated bydecanting the mother liquor and drying under vacuum (0.1 mm, RT). Theyield was 1.48 g (62%) of(+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (5C) (C, H,N). Similarly prepared from 5B and benzaldehyde was(+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (5D) (74%)(C, H, N).

5E. (+-)(2R*,3R*)-2-Amino-2-methyl-1,3-butanediol acetate

To a solution of (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (5B, 22.1g, 0.146 mol) in 95% EtOH (150 mL) was added glacial acetic acid (25 mL)and 10% Pd/C (MCB, 2.0 g). The reduction was carried out in a Parrapparatus at 50 psi of H₂ during a 48 h period at RT. The catalyst wasremoved by filtration through a Millipore® filter, and the solventremoved under vacuum (2 days). The viscous, colorless syrup wasdissolved in abs. EtOH (30 mL). Dilution with abs. Et₂ O (300 mL) gave acloudy liquid which was placed in a refrigerator for two days. Duringthis time, colorless crystals formed. They were washed with Et₂ O anddried in a vacuum oven at RT for two days. The yield of(+-)(2R*,3R*)-2-amino-methyl-1,3-butanediol acetate was 25.6 g (97%) mp117°-121°, (C, H, N).

5F. (+-)(2R*,3S*)-2-Amino-2-methyl-1,3-butanediol acetate

Using the procedure described for 5E(+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (5A) gave(+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate (93%) mp 163°-165°(C, H, N).

5G.(+-)(2R*,2S*)-2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-butanediolhydrochloride

To a RB flask was added (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediolacetate (5F, 4.40 g, 24.55 mmol), NaOCH₃ (Aldrich, 1.33 g, 24.55 mmol)and CH₃ OH (100 mL). After warming to aid solution the solvent wasremoved. To the flask was then added fluoranthene-3-carbaldehyde (1A,5.76 g, 25.0 mmol), p-toluenesulfonic acid (Aldrich, 100 mg) and PhCH₃(250 mL). The flask was then equipped with a magnetic stirring bar,condenser, Dean-Stark trap and N₂ bubbler. The reaction mixture wasstirred for 3 h with azeotropic removal of H₂ O. Most of the PhCH₃ wasthen removed by distillation. The reaction mixture was then cooled to 0°with an ice bath. Abs. EtOH (200 mL) was then added to the mixture andafter further cooling, NaBH₄ (MCB Manufacturing Chemists, Inc., 2909Highland Ave., Cincinnati, OH, 45212, 0946 g, 25.0 mmol). The reactionmixture was allowed to warm to RT and then stirred overnight. Thereaction mixture was treated with 1N NaOH (10 mL) and then the solventsremoved by rotary evaporation. The solid was resuspended with 1N NaOH(3×200 mL) filtered, washed with H₂ O) (2×100 mL) and sucked semidry.The crude white solid was dissolved in excess ethanolic HCl solution(100 mL) filtered and diluted to 2 L with Et₂ O. Filtration and twofurther crystallizations gave after drying(+-)-(2R*,3S*)-2-((3-fluoranthenylmethyl)amino)-2-methyl-1,3-butanediolhydrochloride mp 242°-243° (dec), EtOH/Et₂ O, (C, H, Cl, N).

Note: In other preparations the crude free base was treated with CH₃ SO₃H (99.5%, Morton Thokol, Inc., Alfa Products, P.O. Box 279, 152 AndoverStreet, Danvers, MA, 01923) and purified by the above procedure to givethe corresponding methanesulfonate salt.

EXAMPLE 62-Ethoxymethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediol

6A. 3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole

A mechanically stirred 60% dispersion of NaH in mineral oil (MortonThiokol, Inc.--Alfa Products, P.O. Box 299, 152 Andover Street, Danvers,MA, 01923, 34.0 g, 0.85 mol) was washed with dry hexane to remove theoil and suspended in dry DMF (300 mL). To the mixture was added asolution of 3,5-diphenyl-1H,3H,5H-oxazolo(3,4-c)oxazole-7a(7H)-ethanol(208.2 g, 0.7 mol, prepared by the method of J. Pierce et al., J. Amer.Chem. Soc. 73 2595 (1951)) in dry DMF (300 mL) keeping the reactionmixture between 30°-35°. The salt suspension was stirred at RT for 60min, dilutes with dry DMF (200 mL) to facilitate stirring, cooled, thentreated with ethyl iodide (Aldrich, excess) at such a rate that thereaction temperature was between 20°-35°. The mixture was stirred at RTfor 2 h, then cautiously treated with abs. EtOH (30 mL). The resultingmixture was diluted with Et₂ O (2.5 L) and the resulting solids removedby filtration. The solvent was then removed using a rotary evaporator togive 229.5 g of a yellow oil containing both starting material anddesired product. A solution of the oil in chloroform was mixed with SiO₂(200 g) and the solvent removed. The solid was then added to a column ofSiO₂ (800 g). Elution with the EtOAc/hexane (1:3.5) gave 139.7 g (61.3%)of 3,5-diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole. Ananalytical sample was obtained by recrystallization from hexane, mp83.5°-85°, (C, H, N). The bulk of the material was used without furtherpurification.

6B. 2-Amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4H₂ O

3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole (6A, 136g, 0.42 mol) was dissolved in 6N HCl (400 mL) and the resulting solutionstirred 1.5 h at RT. After extraction with Et₂ O (2×200 mL) to removebenzaldehyde, the aqueous solution was concentrated on a rotaryevaporator to give a colorless oil. This was cooled in an ice bath tofacilitate crystallization. The solid which formed was slurried withcold CH₃ CN, filtered, then washed with Et₂ O and dried in a vacuum ovenat RT to give 71 g (89%) of 2-amino-2-ethoxymethyl-1,3-propanediolhydrochloride.1/4H₂ O mp 78°-79°, (C, H, Cl, N).

6C. 2-Ethoxymethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediolhydrochloride.9/20H₂ O

To a RB flask was added 2-amino-2-ethoxymethyl-1,3-propanediolhydrochloride.1/4H₂ O (6B) and an equimolar amount of sodium methoxide(MCB) and CH₃ OH (100 mL). After warming, the solvent was removed andafter addition of fluoranthene-3-carbaldehyde (1A), the reaction runfollowing the normal reductive amination procedure outlined in (5G) gave2-ethoxymethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediolhydrochloride.9/20H₂ O mp 179°-180°, (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 7 3-Methoxy-2-((3-fluoranthenylmethyl)amino)-2-methyl-1-propanol

7A. 4-Aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane

A solution of 2-amino-2-methyl-1,3-propanediol (Aldrich, 303.4 g, 3.0mol), cyclohexanone (Fisher Scientific Co., 711 Forbes Ave., Pittsburgh,PA, 15219, 294.5 g, 3.0 mol) and PhCH₃ (400 mL) was refluxed forapproximately 2 h with azetropic removal of H₂ O. The material whichcrystallized from the PhCH₃ on cooling was recrystallized 2X from hexaneto give 444.4 g of 4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane(80%) mp 52°-54°, (C, H, N).

7B. 4-Aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane

A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa, 75 g,1.9 mol) was washed with dry hexane to remove the oil and suspended indry DMF (200 mL). To the mixture was added a solution of4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane (7A, 27.8 g, 1.5mol) in dry DMF (200 mL) keeping the reaction mixture temperaturebetween 30°-35°. Small amounts of DMF were added as necessary tofacilitate stirring. The mixture was stirred at RT for 1.5 h, thencooled and treated with methyl iodide (Fisher, 234.2 g, 102.7 mL, 1.65mol) keeping the reaction temperature between 20°-30°. The mixture wasstirred 2 h at RT and slowly treated with abs. EtOH (40 mL), thendiluted with dry Et₂ O (3 L). The reaction mixture was filtered, and thesolvent removed by rotary evaporation. The residue was then fractionallydistilled to give 209.7 g (70.3%) of4-aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane as a colorlessliquid bp 114°/14 mm, (C, H, N).

7C. 2-Amino-3-methoxy-2-methyl-1-propanol

A solution of 4-aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane (7B,299 g, 1.5 mol) and 6N HCl (500 mL) was refluxed for 60 min. On cooling,two layers formed, the upper one containing cyclohexanone was removed byextraction with Et₂ O (2×400 mL). The lower aqueous layer wasconcentrated on a rotary evaporator to give a syrup which then wastreated with excess 50% NaOH. The resulting slurry was extracted withEt₂ O/CH₂ Cl₂ (2:1, 4×500 mL), then with CH₂ Cl₂ (500 mL). The solventwas removed by rotary evaporation to give 198 g of pale oil. Fractionaldistillation of this oil gave 166 g (93%) of2-amino-3-methoxymethyl-1-propanol as a colorless oil bp 94°/17 mm, (C,H, N).

7D. 3-Methoxy-2-((3-fluoranthenylmethyl)amino)-2-methyl-1-propanolhydrochloride

Using the reductive amination procedure outlined in 5G,fluoranthene-3-carbaldehyde (1A) and2-amino-3-methoxy-2-methyl-1-propanol (7C) gave3-methoxy-2-((3-fluoranthenylmethyl)amino)-2-methyl-1-propanolhydrochloride mp 222°-223° (dec), (EtOH/Et₂ O), (C,H,Cl,N).

EXAMPLE 8(1α,2β,3α)-2-((3-Fluoranthenylmethyl)amino)-1,3-cyclohexanediol

8A. 1α,2β,3α-2-Amino-1,3-cyclohexanediol acetate

This compound was prepared by the method of F. Lichtenthaler (Ber. 96,845 (1963)), mp 175°-177°, (C,H,N), (lit. 178°-179°, F. Lichtenthaler,(Ber. 96, 851 (1963)). 8B.(1α,2β,3α)-2-((3-Fluoranthenylmethyl)amino)-1,3-cyclohexanediolhydrochloride

Using the reductive amination procedure outlined for 5G,fluoranthene-3-carbaldehyde (1A) and (1α,2β,3α)-2-1,3-cyclohexanediolacetate (8A) gave (1α,2β,3α)-2-((3-fluoranthenymethyl)amino)-1,3-cyclohexanediol hydrochloride mp 258°-260° C. (dec), (CH₃ OH/Et₂ O),(C,H,Cl,N)

8C. (1α,2β,3α)-2-((3-Fluoranthenylmethyl)amino)-1,3-cyclohexanediolmethanesulfonate

A solution of 8B in CH₃ CH was treated with 5 equivalents of 1N NaOH.The free base which formed was filtered, washed with H₂ O and dried.Using the procedure in 5G was converted to its free base. Addition of anequivalent of methanesulfonic acid (Aldrich, 99.5%) followed byrecrystallization (EtOH/Et₂ O) gave(1α,2β,3α)-((3-fluoranthenylmethyl)amino)-1,3-cyclohexanediolmethanesulfonate mp 214°-216° (dec), (C,H,N,S).

EXAMPLE 9 2-((3-Fluoranthenylmethyl)amino)-2-isopropyl-1,3-propanediol

9A. 2-Isopropyl-2-nitro-1,3-propanediol

A solution of 2-methyl-1-nitropropane (38.7 g, 0.375 mol, prepared bythe procedure of N. Kornblum, B. Tunbe, and H. Ungnade, J. Amer. Chem.Soc., 76, 3209 (1954)) and NEt₃ (Eastman, 3.79 g, 0.375 mol) in CH₃ OH(50 mL) was added dropwise 37% aqueous formaldehyde solution(Mallinckrodt, 76.2 g, 0.938 mol) at a rate such that the reactionmixture temperature did not exceed 30°. After 72 h, the solution wasconcentrated under vacuum and the residue was dissolved in H₂ O (250mL). The solution was continuously extracted for 1 h with CH₂ Cl₂ (1 L).The CH₂ Cl₂ solution was dried (MgSO₄), filtered, and concentrated togive 53.3 g (87%) of 2-isopropyl-2-nitro-1,3-propanediol, as a waxy,white solid mp 67°-72° C. (lit. mp 87°-88° B. M. Vanderbilt and H. B.Hass, Ind. Eng. Chem. 32, 34 (1940). In our hands this procedure failedto give the desired compound).

B.10-((1,1-Bis(hydroxymethyl)ethylamino)methyl)-9-anthracenecarbonitrilehydrochloride

9B. 2-Amino-2-isopropyl-1,3-propanediol acetate

Using the procedure in 5E, 2-isopropyl-2-nitro-1,3-propanediol acetatemp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337(1975) report the synthesis of this compound as the free base (mp70°-72°)).

9C. 2-((3-Fluoroanthenylmethyl)amino)-2-isopropyl-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined for 5G,fluoranthene-3-carbaldehyde (1A) and 2-amino-2-isopropyl-1,3-propanediolacetate.1/4 H₂ O(2-((3-fluoranthenylmethyl)amino)-2-isopropyl-1,3-propanediolhydrochloride mp 216°-217° (dec), (EtOH/Et₂ O), (C,H,Cl,N).

EXAMPLE 10 2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,4-butanediol

10A. Ethyl N-benzylidene-l-alaninate

Ethyl N-benzylidene-l-alaninate was prepared according to the gerneralprocedure of G. Stork et al., J. Org. Chem. 41 349 (1976), bp98°-100°/0.4 mm (lit. 100°/0.3 mm, A. Calcagni et al., Synthesis 445(1981)). 10B. 2-(2-Iodoethoxy)tetrahydro-2-H-pyran

Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was addeddropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol)in Et₂ O (1L) containing 0.1 g of p-toluenesulfonic acid (Eastman). Thesolution was then stirred for 1 h at 5°. Solid K₂ CO₃ (Mallinckrodt, 5g) was then added to the reaction mixture and the resulting suspensionstirred an additional 1 h at RT. The reaction was then filtered and theremaining solid washed with Et₂ O (1 L). The organic solutions werecombined and concentrated rotary evaporation (in a flask washed with 1%NEt₃ in H₂ O). The crude 2-(2-iodoethoxy)-tetrahydro-2-H-pyran (˜100 g,68.9%) was used without further purification.

10C. Ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate

A solution of lithium diisopropylamide was prepared by dropwise additionof n-BuLi (Aldrich 1.6 M in hexane, 228 mL, 0.365 mol) to a solution ofdiisopropylamine (Aldrich, 51.6 g, 0.51 mol) in a mixture of dry THF(700 mL) and dry HMPA (Aldrich, 40 mL) kept at 30°-40°. The solution wasthen cooled to -70° and a solution of ethyl N-benzylidene-l-alaninate(10A, 74.9 g, 0.365 mol) was added dropwise to the solution allowing thereaction mixture warm to -20° for several min. The resulting redsolution was then cooled to -70°. 2-(2-Iodoethoxy)tetrahydro-2-H-pyran(10B, 98.1 g, 0.383 mol) was then added to the solution at such a ratethat the temperature in the reaction mixture did not rise above -65°.

EXAMPLE 272-((10-Methoxy-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride

A. 10-Methoxy-9-anthracenecarbaldehyde

A 2 L round bottom flask fitted with distilling head, thermometer, andcondenser was charged with 15-crown-5 (Aldrich, 25.89 g, 0.118 mol),NaOCH₃ (Aldrich, 7.62 g, 0.141 mol), and CH₃ OH (50 mL). After 5 minutes10-chloro-9-anthracenecarbaldehyde (Aldrich, 28.4 g, 0.118 mol) and 900mL of dry PhCH₃ were added to the clear colorless solution. The solventwas distilled off until the head temperature reached 108° (300 mL).Additional dry PhCH₃ was added to give at total of 1 L volume. Thereaction mixture was refluxed for 4 h, cooled and poured onto a largeplug of SiO₂ (1000 g) in a sintered glass funnel. The crude product waschromatographed using PhCH₃ as eluent (5 L). The fractions (250 mL)containing the product were combined (-3 L) and the solvent volumereduced to 500 mL. The shiny golden crystals which formed were filteredto give after drying at 50° 15.6 g of material. The volume of thefiltrate was reduced to 200 mL and more material fell out of solutionand was filtered and dried to give 6.91 g of additional material. Thetwo crops were combined to give 22.51 g (81%) of10-methoxy-9-anthracenecarbaldehyde which was used without furtherpurification. Recrystallization gave analytically pure material mp164.5°-166.5, (PhCH₃), (C, H), (lit. mp 165°, J. B. Conant and M.Bramann, J. Amer. Chem. Soc. 50 2305 (1928)).

B. 2-((10-Methoxy-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in 1B, 10-methoxy-9-

The solution was allowed to warm slowly to RT and stirred for 14 h. Thevolume of the solution was reduced to 300 mL by a stream of dry N₂during the last few hours to facilitate the final workup. The reactionwas quenched with satd. NaCl (800 mL) and diluted with Et₂ O (800 mL).The Et₂ O was removed and the aqueous layer extracted with hexane (500mL). The Et₂ O and hexane layers were combined and dried (Na₂ SO₄). Thesolution was filtered and the solvent removed to give 124 g of crude redoil. Bulb to bulb distillation (in 1% aq. NEt₃ washed glassware) (210°bath temperature/0.3 mm) gave 95 g of ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyratewhich was homogeneous by vpc and gave acceptable NMR and mass spectra.It was stored under N₂ in the refrigerator and was used without furtherpurification.

10D. 2-Benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol

A solution of ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate(10C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspensionof lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred indry THF (1 L) at such a rate to maintain a gentle reflux. After theaddition was complete the mixture was refluxed for 4 h. The reactionmixture was cooled and treated successively with H₂ O (23 mL), 15N NaOH(23 mL) and H₂ O (45 mL). The solid was removed by filtration and washedwith THF (200 mL). The organic layers were combined and concentrated byrotary evaporation to give2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g,92.0%) as a thick oil which was used without further purification.

10E. 2-Benzylamino-2-methyl-1,4-butanediol

The crude2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (10D,80.1 g, 0.273 mol) was dissolved in 3N HCl (128 mL). After 5 min themixture was washed with Et₂ O (200 mL). The aqueous solution wasconcentrated by rotary evaporation to give a thick oil which was cooledand basified with excess 50% NaOH. The oily amine which formed wasextracted with Et₂ O (3×200 mL). The Et₂ O extracts were combined andconcentrated to give 63.6 g of a thick oil. Distillation gave 49.8 g(94%) of 2-benzylamino-2-methyl-1,4-butanediol as a pale yellow oil (bp168°-170°/0.35 mm) (C, H, N)

10F. 2-Amino-2-methyl-1,4-butanediol hydrochloride

2-Benzylamino-2-methyl-1,4-butanediol (10E, 31.08 g, 0.149 mol) wasdissolved in 95% EtOH (240 mL) containing conc. HCl (21 mL, 0.25 mol)and 5% Pd/C (10.0 g) and reduced in a Parr apparatus at 40 psi over 37 hat RT. The catalyst was then removed by filtration and the solventremoved by rotary evaporation (bath at 60°) to give 20.91 g of2-amino-2-methyl-1,4-butanediol hydrochloride (90.2%) as a clear, thick,colorless oil with acceptable NMR and mass spectra. It was used withoutfurther purification. This compound has been reported as its acetatesalt (G. Cardillo et al., Chem. Commun. 1308, 1982), but no data wasgiven. Attempts to duplicate the latter procedure were unsuccessful.

10G. 2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,4-butanediolhydrochloride 11/20H₂ O

To a RB flask was added 2-amino-2-methyl-1,4-butanediol hydrochloride(10F), an equimolar amount of sodium methoxide (MCB) and enough CH₃ OHto form a solution when warmed. The solvent was then removed by rotaryevaporation and after addition of fluoranthene-3-carbaldehyde (1A), thereaction run following the normal reductive amination procedure outlinedin 5G to give 2-((3-fluoranthenylmethyl)amino)-2-methyl-1,4-butanediolhydrochloride.11/20H₂ O mp 210°-212° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 112-(((4-Ethyl-3-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate

11A. Formylation of 3-ethylfluoranthene

3-Ethylfluoranthene (Cambridge Chemical, Inc., 202 E. Smith Street,Milwaukee, WI, 53207, 70 g, 0.304 mol) was formylated according to theprocedure outlined in 1A, except that CH₂ Cl₂ (1 L) was used as thereaction solvent. Chromatography on a plug of SiO₂ (1 kg) yielded threepartially purified products, each of which was rigorously purified bypreparative HPLC using PhCH₃ as the eluting solvent. Each of the threeproducts were isomeric mixtures as described below.

11B. 3- and 4-Ethylfluoranthene-7-carbaldehyde, 5.0 g (6%), (Rf=0.55,SiO₂, PhCH₃), (C, H).

11C. 4-Ethylfluoranthene-3-carbaldehyde and3-ethylfluoroanthene-2-carbaldehyde, 4.7 g (6%), (Rf=0.49, SiO₂, PhCH₃),(C, H).

11D. 3- and 4-Ethylfluoranthene-8-carbaldehyde, 47.3 g (60%), (Rf=0.38,SiO₂, PhCH₃), (C, H).

11E. 4-Ethylfluoranthene-3-carbaldehyde

The mixture 11C (4.7 g) was recrystallized 2× from CH₂ Cl₂ /hexane toyield 1.83 g (2% from 3-ethylfluoranthene) of4-ethylfluoranthene-3-carbaldehyde mp 113.5°-116°, (C, H).

11F.2-(((4-Ethyl-3-fluoroanthenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in 5G,4-ethyl-fluoranthene-3-carbaldehyde (11E) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-(((4-ethyl-3-fluoroanthenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate mp 198°-199°, (EtOH/hexane), (C, H, N, S).

EXAMPLE 12 2-((3-Fluoranthenylmethyl)amino)-2-methyl-1-propanolhydrochloride

Using the reductive amination procedure outlined in 1D,3-fluoranthenecarbaldehyde (1A) and 2-methyl-2-aminopropanol (Aldrich)gave 2-((3-fluoranthenylmethyl)-amino)-2-methyl-1-propanolhydrochloride, mp 288°-290° (dec), (CH₃ OH/Et₂ O), (C, H, Cl, N).

EXAMPLE 13 2-((8-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in 1D,8-fluoranthenecarbaldehyde (1C) and 2-methyl-2-amino-1,3-propanediol(Aldrich) gave 2-((8-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride mp 233°-234.5° (dec), (CH₃ OH/Et₂ O), (C, H, Cl, N).

EXAMPLE 142-(((3-Chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and2-(((4-Chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol

14A. 3-Chlorofluoranthene

Fluoranthene (Aldrich, 99 g, 0.49 mol) dissolved in 2 L of HOAc (at 40°)treated dropwise with SO₂ Cl₂ (Eastman, 47 mL, 0.59 mol), then heated at100° for 1 h gave a mixture of dichloro- and monochloro- products plusstarting material. The dichloro- material (predominantly1,3-dichlorofluoranthene, 16.8 g, 13%, mp 179°-182°) precipitated uponcooling overnight and was isolated by filtration. The filtrate wasstripped to dryness and dissolved in hexane, then eluted through 500 gof SiO₂ with hexane to remove polar impurities. The hexane eluates werereduced to 200 mL to yield a precipitate that was recrystallized twicefrom CH₂ Cl₂ /hexane to afford 31.8 g of slightly impure3-chlorofluoranthene (28%), mp 93°-96°. A sample purified by preparativeHPLC using hexane as the eluting solvent gave pure 3-chlorofluoranthene,mp 95°-98°, (lit. mp 96°-98°, A. Sieglitz and H. Troster, Berichte, 96,2577 (1963) (C, H, Cl).

14B. 3- and 4-Chlorofluoranthene-8-carboxaldehyde

3-Chlorofluoranthene (14A, 30 g, 0.13 mol) was formylated according tothe procedure outlined in 1D. Chromatography on a plug of SiO₂ (500 g)using PhCH₃ as the eluting solvent gave 14.2 (42%) of purified material,a mixture of 3- and 4-chlorofluoranthene-8-carbaldehyde mp 165°-183°,(C, H, Cl).

14C.2-(((3-Chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and2-(((4-Chloro-8-fluoranthenyl)methyl)amino-2-methyl-1,3-propanediolhydrochloride

Using the reduction amination procedure outlined in 1A the mixture of 3-and 4-chloro-fluoranthene-8-carbaldehydes (14B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a mixture of2-(((3-chloro-8-fluoranthenyl)-methyl)amino)-2-methyl-1,3-propanedioland 2-(((4-chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediolhydrochloride, mp 224°-225° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 152-(((3-Ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and2-(((4-Ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol

15A. 3- and 4-Ethylfluoranthene-7-carbaldehydes

15B. 4-Ethylfluoranthene-3-carbaldehyde and3-ethylfluoranthene-2-carbaldehyde

15C. 3- and 4-Ethylfluoranthene-8-carbaldehydes

3-Ethylfluoranthene (Cambridge Chemical, Inc., 70 g, 0.304 mol) wasformylated according to the procedure outlined in 1A, except that CH₂Cl₂ (1 L) was used as the reaction solvent. Chromatography on a plug ofSiO₂ (1 kg) yielded three partially purified products, eachh of whichwas rigorously purified by preparative HPLC using PhCH₃ as the elutingsolvent. Each of the three products was an isomeric mixture as describedbelow.

15A. 3- and 4-Ethylfluoranthene-7-carbaldehyde, 5.0 g (6%) (Rf=0.55,SiO₂, PhCH₃), (C, H).

15B. 4-Ethylfluoranthene-3-carbaldehyde and3-ethylfluoranthene-2-carbaldehyde, 4.7 g (6%), (Rf=0.49, SiO₂, PhCH₃),(C, H).

15C. 3- and 4-Ethylfluoranthene-8-carbaldehyde, 47.3 g (60%), (Rf=0.38,SiO₂, PhCH₃), (C, H).

15D. 4-Ethylfluoranthene-3-carbaldehyde

Product mixture 15B (4.7 g) was recrystallized twice from CH₂ Cl₂/hexane to yield 1.83 g (2% from 3-ethylfluoranthene) of4-ethylfluoranthene-3-carbaldehyde mp 113.5°-116°, (C, H), (Rf=0.31,SiO₂, PhCH₃).

15E. 2-(((3-Ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanedioland 2-(((4-Ethyl-8-fluoroanthenyl)methyl)amino)-2-methyl-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in 1D, the mixture of3- and 4-ethyl-8-fluoranthenecarbaldehyde (15C) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-(((3-ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and2-(((4-ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediolhydrochloride mp 182°-183° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

Antitumor Screening Results

Methods for evaluating the antitumor activity of these compounds areessentially those used in the Tumor Panel by the DevelopmentalTherapeutics Program, Division of Cancer Treatment, National CancerInstitute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p.165, Academic Press (1979). Some modifications, in dose level andschedule have been made to increase the testing efficiency.

EXAMPLE 16 Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing 20±3 g are used for this test.Control and test animals are injected intraperitoneally with asuspension of ˜10⁶ viable P388/0 tumor cells on day 0. In each test,several dose levels which bracket the LD₂₀ of the compound areevaluated; each dose level group contains six animals. The testcompounds are prepared either in physiologic saline containing 0.05%Tween 80 or distilled water containing 5% dextrose and are administeredintraperitoneally on days 1, 5, and 9 relative to tumor implant. Dosesare on a mg/kg basis according to individual animals' body weights. Theday of death for each animal is recorded, the median identified for eachgroup and the ratios of median survival time for treated (T)/control (C)groups are calculated. The criterion for activity is T/C×100≧120%.Results of P388/0 testing are summarized in Table I below.

                  TABLE 1                                                         ______________________________________                                        P388/0 SCREENING RESULTS                                                                            T/C × 100%                                        Compound of                                                                             Optimal Dose                                                                              (Excluding 30 Day                                       Example No.                                                                             (mg/kg)     Survivors     LD.sub.20.sup.A                           ______________________________________                                        1D        90          +270          90                                         2        46          +250          53                                         3        90          +280          80                                         4        123         +242          100                                       7D        150         +260          180                                       5G        60          +255          40                                        6C        95          +260          95                                        8B        452         +225          (675)                                     9C        210         +260          (675)                                     10G       86          +230          70                                        12        100         +220          150                                       ______________________________________                                         .sup.A Values in parentheses are the highest nontoxic dose where the          LD.sub.20 was not determined.                                            

EXAMPLE 17 Lymphocytic Leukemia L1210 Test

The protocol for this test is identical to that for P388/0, except thatthe number of L1210 cells implanted on day 0 is 10⁵ /mouse. The mouseCD2-F₁ strain is used, and the criterion for activity is T/C×100≧125%.Results of L1210 testing are summarized in Table II below.

                  TABLE II                                                        ______________________________________                                        Screening Results for L1210                                                                          T/C × 100%                                       Compound of   Dose     Excluding 30 day                                       Example No.   (mg/kg)  Survivors                                              ______________________________________                                        1D            75       +258                                                   ______________________________________                                    

EXAMPLE 18 Melanotic Melanoma B16

B6C3-F₁ mice of the same sex, weighing 20±3 g, are used for this test. Asuspension of B16 cells is prepared from a non-necrotic portion of solidtumor tissue obtained from a passage mouse. One gram of tumor ishomogenized in 9 mL ice-cold Earle's salts solution and filtered through1000 mesh screen to remove debris. 0.5 mL of the resulting brei isinjected intraperitoneally into each animal. Dosing is carried out as inthe P388/0 and L1210 tests. Days of death are recorded for a 60 dayperiod and T/C ratio calculated as in the P388/0 and L1210 tests. Thecriterion for activity is T/C×100>125%. The results of B16 testing aresummarized below in Table III.

                  TABLE III                                                       ______________________________________                                        Screening Results for B16 Melanoma                                                                   T/C × 100%                                       Compound of   Doe      Excluding 60 day                                       Example No.   (mg/kg)  Survivors                                              ______________________________________                                        1D            85       +210                                                   4             100      +160                                                   2             25       +194                                                   3             60       +172                                                   ______________________________________                                    

EXAMPLE 19 Lewis Lung Carcinoma Test

This tumor arose spontaneously in the lung of C57B1/6 mouse and ismaintained by subcutaneous passage in that strain. The solid tumor isexcised aseptically and placed in sterile saline. Pieces of viable tumortissue are minced finely with scissors and forced through a 200 meshstanless steel screen to disaggregate the tumor cells into a suspension.10⁶ Viable cells are injected intravenously into the tail vein of BD-F₁,mice of the same sex weighing 20±3 g. In each test, several dose levelswhich bracket the LD₂₀ for the compound are evaluated. Ten animals areincluded in each dose level group, and twenty animals in the untreatedcontrol group. The test compounds are prepared and administered on days1, 5, and 9 as in the P388/0 protocol. The day of death for each animalis recorded, the median identified for each group and the ratios ofmedian survival time for treated (T)/control (C) groups are calculated.The criterion for activity is T/C×100≧140%. The results of Lewis Lungtesting are summarized in Table IV.

                  TABLE IV                                                        ______________________________________                                        Screening Results for Lewis Lung                                                                     T/C × 100%                                       Compound of   Dose     Excluding 60 day                                       Example No.   (mg/kg)  Survivors                                              ______________________________________                                        1             85       +222                                                   ______________________________________                                    

EXAMPLE 20 Colon 38 Carcinoma Test

This chemically-induced tumor arose in a C57B1/6 mouse and is maintainedas a solid tumor in that mouse strain. The subcutaneously growing solidtumor is aseptically excised from passage mice and placed in sterilesaline. The tumour is trimmed free of visible necrotic and connectivetissue, then divided into 2-3 mm cubes. A cube is implantedsubcutaneously in the ventral thoracic region with a sterile trochar onday 0. In each test several dose levels which bracket the LD₂₀ for thecompound are evaluated. Ten animals are included in each dose levelgroup and thirty animals in the untreated control group. The testcompounds are prepared either in physiologic saline containing 0.05%Tween 80 or distilled water containing 5% dextrose and are administeredintraperitoneally on days 1, 5 and 9 after tumor implant. Doses are on amg/kg basis according to individual animals' body weights. At day 20,the animals are sacrificed and the longest (L) and shortest (W)dimensions of each tumor measured wih vernier calipers. Tumor weight iscalculated from the formula ##EQU1## The criterion for activity isT/C×100≦42%. The results of Colon 38 testing are summarized in Table V.

                  TABLE V                                                         ______________________________________                                        Screening Results for Colon 38                                                Compound of    Dose                                                           Example No.    (mg/kg)  T/C × 100%                                      ______________________________________                                        1              65       23                                                    ______________________________________                                    

EXAMPLE 21 M5076 Sarcoma Test

This sarcoma arose as a solid tumor in the ovary of a C57B1/6 mouse andwas subsequently converted to the ascitic form for intraperitoneal use.The protocol for this test is identical with that for P388/0. TheB6C3-F₁ mouse strain is used and the criterion for activity isT/C×100≧125%. Results of M5076 testing are summarized in Table VI below.

                  TABLE VI                                                        ______________________________________                                        Screening Results for M5076                                                   Compound of    Dose                                                           Example No.    (mg/kg)  T/C × 100%                                      ______________________________________                                        1D             85       +162                                                  ______________________________________                                    

EXAMPLE 22 Herpes simplex 1/vero Test

Antiviral testing against Herpes simplex 1/vero was done using plaqueinhibition methods as outlined in P. Collins and D. J. Bauer, Proc. N.Y.Acad. Sci. 284, 49(1977) and by plaque reduction methods as outlined inP. Collins and D. J. Bauer, J. Antimicrobial Chemotherapy 3, SupplementA, 73(1977). The column headings labeled Score, Toxicity, and Zone ofInhibition refer to the plaque inhibition screen while the IC₅₀ headingto the plaque reduction screen.

                  TABLE VII                                                       ______________________________________                                        Results of Antiviral Screening Against herpes simplex 1/vero                  Compound of                  Zone of                                          Example No.                                                                             Score.sup.A                                                                            Toxicity  Inhibition.sup.B                                                                       IC.sub.50.sup.B                         ______________________________________                                         4        -3       Y                                                          8B        -3       Y                  17.4                                    12        -3       Y         40(VTat28)                                       13        -3       Y                  6.10                                    ______________________________________                                         .sup.A Score: O = no inhibition, -1 = 1-25% inhibition, -2 = 26-50%           inhibition -3 = 51-75% inhibition, -4 = 76-100% inhibition                    .sup.B ST = slight toxicity, T = toxic                                   

EXAMPLE 23 Candida albicans Test

Antifungal testing against Candida albicans (CN 1863) was done withslight modifications using a combination of broth and agar dilutionassays as outlined in Laboratory Handbook of Medical Mycology, Chapter6, pages 441-446, M. R. McGinnis, Academic Press, New York, N.Y, 1980

                  TABLE VIII                                                      ______________________________________                                        Results of Antifungal Testing Against Candida albicans (CN1863)                      Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                               1D       30                                                                    2       30                                                                    3       30                                                                   5G       30                                                                   12       30                                                            ______________________________________                                         Medium: Wellcotest ® sensitivity test agar plus 7% lysed horse blood.

Antibacterial Screening

Antibacterial testing against Mycoplasma smegmatis (S3264) andStreptococcus pyrogenes (CN10) was done with slight modifications usingstandard agar dilution assays as outlined in Manual of ClinicalMicrobiology Second Ed., E. H. Lennette, E. H. Spaulding and J. P.Truant Eds., American Society for Microbiology, Washington, DC, 1974.

EXAMPLE 24

                  TABLE IX                                                        ______________________________________                                        Results of AntibacterialTesting Against                                       Streptococcus pyogenes (CN10)                                                        Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                                1D      ≦10                                                            2       10                                                                    3       10                                                                   10G      30                                                                   12       10                                                            ______________________________________                                    

EXAMPLE 25 Mycoplasma smegmatis Test

                  TABLE X                                                         ______________________________________                                        Results of Antibacterial Screening Against                                    Mycoplasma smegmatis (53264)                                                         Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                                1D      ≦10                                                            2       30                                                                    3       10                                                                   10G      10                                                                   12       10                                                            ______________________________________                                    

EXAMPLE 26 Eimeria tenella Testing

Antiprotozoal testing against Eimeria tenella was done using methodsoutlined in V. S. Latter and D. Wilson, Parasitology 79, 169(1979)

                  TABLE XIII                                                      ______________________________________                                        Results of Antiprotozoa Screening Against                                     Eimeria tenella (in vitro)                                                    Compound of      Dose                                                         Example No.      (mg/L)  Result.sup.A                                         ______________________________________                                        1D               0.31    -4                                                   ______________________________________                                         .sup.A Screen Code 0 = no inhibition, -1 = 25% inhibition, -2 = 26-50%        inhibition, -3 = 51-75% inhibition, -4 = 76-100% inhibition              

EXAMPLE 27 LD₅₀ Tests

                  TABLE XIV                                                       ______________________________________                                        LD.sub.50 Values for Selected Compounds                                       (IP single dose - CD-1 Male Mouse)                                            Compound of    LD.sub.50                                                      Example No.    (mg/kg)                                                        ______________________________________                                        1D             82                                                             ______________________________________                                    

EXAMPLE 28 Formulation Examples

A. Tablet

Compound of Formula I: 500.0 mg

Pregelatinized Corn Starch: 60.0 mg

Sodium Starch Glycolate: 36.0 mg

Magnesium Stearate: 4.0 mg.

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, pregelatinized corn starch and sodium starchglycolate. The powders are wetted with purified water to form granules.The granules are dried and mixed with the magnesium stearate. Theformulation is then compressed into tablets weighing approximately 600mg each.

B. Tablet

Compound of formula (I): 500.0 mg

Corn Starch: 70.0 mg

Lactose: 83.8 mg

Magnesium Stearate: 4.2 mg

Polyvinylpyrrolidone: 14.0 mg

Stearic Acid: 28.0 mg.

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, corn starch and lactose. The powders are wettedwith a solution of polyvinylpyrrolidone dissolved in purified water anddenatured alcohol to form granules. The granules are dried and mixedwith the powdered stearic acid and magnesium stearate. The formulationis then compressed into tablets weighing approximately 700 mg each.

C. Capsules

Compound of formula (I): 500.0 mg

Corn Starch: 50.0 mg

Magnesium Stearate: 3.0 mg.

The finely divided compound of formula (I) is mixed with powdered cornstarch and wetted with denatured alcohol to densify the powder. Thedried powder is mixed with stearic acid and filled into hard-shellgelatin capsules.

D. Syrup

Compound of formula (I): 250.0 mg

Ethanol: 250.0 mg

Glycerin: 500.0 mg

Sucrose: 3,500.0 mg

Flavoring Agent: q.s.

Coloring Agent: q.s.

Preserving Agent: 0.1%

Purified Water: q.s. to 5.0 mL.

The compound of formula (I) is dissolved in the ethanol, glycerin, and aportion of the purified water. The sucrose and preserving agent aredissolved in another portion of hot purified water, and then thecoloring agent is added and dissolved. The two solutions are mixed andcooled before the flavoring agent is added. Purified water is added tofinal volume. The resulting syrup is throughly mixed.

E. IV Injection

Compound of formula (I): 5.0 mg

Glycerin: q.s. for isotonicity

Preservative: 0.1%

Hydrochloric Acid or Sodium Hydroxide: as needed for pH adjustment

Water for Injection: q.s. to 1 mL

The compound of formula (I) and preservative is added to the glycerinand a portion of the water for injection. The pH is adjusted withhydrochloric acid or sodium hydroxide. Water for injection is added tofinal volume and solution is complete after thorough mixing. Thesolution is sterilized by filtration through a 0.22 micrometer membranefilter and aseptically filled into sterile 10 mL ampules or vials.

What is claimed is:
 1. A pharmaceutical formulation containing acompound of formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof, the compound of formula (I)including its ethers containing no more than 30 carbon atoms in total);ethers, esters thereof; acid addition salts thereof; wherein Ar is afluoranthene ring optionally substituted by one or two substituents. Thesubstituents will contain not more than four carbon atoms in total whentaken together being the same or different and are selected fromhalogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substitutedby hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂alkoxy; a group S(O)_(n) R² wherein n is an integer 0,1 or 2 and R² isC₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; or thefluoranthene ring is optionally substituted by a group NR³ R⁴ containingnot more than 5 carbon atoms wherein R³ and R⁴ are the same or differentand each is a C₁₋₃ alkyl group; R¹ contains not more than eight carbonatoms and is a group ##STR9## wherein m is 0 or 1;R⁵ is hydrogen; R⁶ andR⁷ are the same or different and each is hydrogen or C₁₋₃ alkyloptionally substituted by hydroxy (providing that at least one hydroxygroup is present); R⁸ and R⁹ are the same or different and each ishydrogen or C₁₋₃ alkyl; --C--C-- is a five- or six-membered saturatedcarbocyclic ring; R¹⁰ is hydrogen, methyl or hydroxymethyl; R¹¹, R¹² andR¹³ are the same or different and each is hydrogen or methyl; R¹⁴ ishydrogen, methyl, hydroxy, or hydroxymethyl with a pharmaceuticallyacceptable carrier in the form of a tablet, capsule, syrup, or asolution for injection except that the formulation does not include2-((3-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol or apharmaceutically acceptable salt thereof.
 2. The method of reducing thecells of a susceptible tumor which comprises contacting said susceptibletumor cells with a tumor reducing amount of the compound or salt of theformulation of claim
 1. 3. A method of claim 2 for a compound of formula(I)wherein Ar is 3- or 7-fluoranthenyl, ##STR10## R¹ is ##STR11##wherein m is 0; R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen,C₁₋₃ alkyl or CH₂ OH; R¹⁸ is hydrogen or methyl; or a monomethyl ormonoethyl ether thereof containing no more than 28 carbon atoms intotal; acid addition salts thereof.
 4. A method of claim 3wherein R¹⁶ isCH₂ OH or CH(CH₃)OH and R¹⁷ is hydrogen, methyl, ethyl or CH₂ OH; Ar is3-fluoranthenyl; acid addition salts thereof.
 5. A method of claim 4wherein R¹ is a diol of the structure ##STR12## wherein R¹⁹ is hydrogenor methyl and R²⁰ is hydrogen, methyl or ethyl; acid addition saltsthereof.
 6. A method of claim 5 wherein R²⁰ is methyl; acid additionsalts thereof.
 7. A method of claim 2 wherein the compound of formula(I) is a methanesulfonic, hydrochloric, ethanesulfonic, lactic, citricor isethionic acid addition salt.
 8. A method of claim 2 wherein acompound of formula (I) is selectedfrom2-((3-Fluoranthenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol,2-Ethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediol,2-((7-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol,3-Methoxy-2-((3-fluoranthenylmethyl)amino)-2-methyl-1-propanol,(+-)(2R*,3S*)-2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,3-butanediol,2-Ethoxymethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediol,(1α,2β,3α)-2-((3-Fluoranthenylmethyl)amino)-1,3-cyclohexanediol,2-((3-Fluoranthenylmethyl)amino)-2-isopropyl-1,3-propanediol,2-((3-Fluoranthenylmethyl)amino)-2-methyl-1,4-butanediol,2-((4-Ethyl-3-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol,2-((3-Fluoranthenylmethyl)amino)-2-methyl-1-propanol,2-((8-Fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol,2-(((3-Chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and2-(((4-Chloro-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol,2-(((3-Ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol and1-(((4-Ethyl-8-fluoranthenyl)methyl)amino)-2-methyl-1,3-propanediol;acid addition salts thereof.
 9. A method of claim 8 wherein the compoundof formula (I) is a methanesulfonic, hydrochloric, ethanesulfonic,lactic, citric or isethionic acid addition salt.